Thio-derivatives of 1,2-benzothiazine dioxides

ABSTRACT

THE COMPOUNDS HEREIN ARE 1,2,3,4-TETRAHYDRO-11-HYDROXYPYRAZINO(1,2-B)-1,2-BENZOTHIAZIN-1(2H)-ONE 6,6DIOXIDES, USEFUL FOR THEIR ULTRAVIOLET ABSORPTION AND CENTRAL NERVOUS SYSTEM DEPRESSANT ACTIVITY.

United States Patent Office.

3,787,402 THIO-DERIVATIVES F 1,2-BENZOTHIAZINE DIOXIDES Chris Royce Rasmussen Ambler, Pa., assignor to McNeil Laboratories, Inc.

No Drawing. Filed Oct. 2, 1972, Ser. No. 294,121 Int. Cl. C07d 93/02 US. Cl. 260-243 R 4 Claims ABSTRACT OF THE DISCLOSURE The compounds herein are 1,2,3,4tetrahydro-1l-hydroxypyrazino[1,2-b]-1,2-benzothiazin1(2g) one 6,6- dioxides, useful for their ultraviolet absorption and central nervous system depressant activity.

DESCRIPTION OF THE INVENTION This invention relates to novel 1,2-benzothiazine dioxides having the formula:

N-CHaCH -SR S 0 a V wherein R is a member of the group consisting of loweralkyl, phenyl, substituted phenyl, and phenyl-loweralkyl. The term substituted pheny is meant to include phenyl substituted with one or more, preferably 1 to 2, of the following: loweralkyl, loweralkoxy, and halo. As used herein loweralkyl and loweralkoxy mean straight or branched chain saturated aliphatic hydrocarbons having from 1 to about 5 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, pentyl, and the like; and the corresponding alkoxy derivatives, for example, methoxy, ethoxy, propoxy, isopropoxy, pentoxy, and the like. The term halo is meant to include fluoro, chloro, bromo, and iodo.

The compounds of Formula I are prepared from (1,2, 3,4-tetrahydro l1 hydroxy-1-oxopyrazino[1,2- b]-1,2- benzothiazin-2-yl)ethyl methanesulfonate 6,6-dioxide (II), described in my copending application Ser. No. 294,126 entitled, Novel 1,2-Benzothiazine Dioxides and Precursors Therefor, filed on the same date as the instant application, by reacting the latter with a slight molar excess each of sodium methoxide and a mercaptan of formula RSH, wherein R is as previously defined. The reaction is conducted in a suitable organic solvent, such as, for example, an ether, e.g., ethyl ether, dioxane, tetrahydrofuran, and the like; a loweralkanol, e.g., ethanol, isopropanol, butanol, and the like; dimethylformamide; dimethylsulfoxide; and the like. This reaction may be illustrated as follows:

I N-CHzCHzOS 02C Ha NaOMe R SH (I) 3,787,402 Patented Jan. 22, 1974 resins such as, for example, polystyrene, polyethylene, polypropylene, polyacrylics (e.g., methacrylate resins, polyacrylamides, polyacrylonitrile fibers, etc.), polyamide (e.g., nylon) fibers, and polyester fibers. The inclusion of about -0.015.0 percent of the absonber, based on the polymer weight, is usually sutficient to render protection against U.V. light, such as in plastic films, filters, etc. The absorber may be incorporated into the mixture of monomers before polymerization to form the polymer or it may be incorporated into the polymer at other stages during its handling, as by milling into the polymer together with other compounding ingredients, or during the spinning of the polymer into fibers, etc.

These compounds are also useful for their central nervous system depressant activity as indicated by such symptoms as ataxia, decrease in motor activity, and loss of righting reflex in mice after intraperitoneal (i.p.) administration of the Compounds I when tested at doses of about mg./ kg. body weight.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

EXAMPLE I 2- Z-benzylthioethyl) 1,2,3 ,4-tetrahydro-1 l-hydroxypyrazinol[ 1,2-b]-1,2-benzothiazin-1 (2g) -one 6,6-dioxide To a solution of sodium methoxide in dimethylformamide (prepared by dissolving 0.92 g. (0.0395 mole) of sodium in 20 ml. of methanol, removing the excess methanol in vacuo, and adding 20 ml. of dimethylformamide) is added 4.9 g. (0.039 mole) of a-thiotoluene with stirring. Then 15.0 g. (0.038 mole) of (1,2,3,4-tetrahydroll-hydroxy 1 oxopyrazino[1,2 b]-l,2-benzothiazin-2- yl)ethyl methanesulfonate 6,6-dioxide is added slowly with stirring. After the addition is complete, the solvent is removed in vacuo, and acetone and water are added to the residue, giving the product, M.P. 106-108 C. Recrystallization of this crude product from acetonewater yields the pure product, 2-(2benzylthioethyl)-l,2, 3,4-tetrahydro 11 hydroxypyrazino[1,2- b]-1,2-benzothiazin-1(2))one 6,6-dioxide, M.P. 114-1l5 C.

Analysis.Calcd. for C H N O' S (percent): C, 57.68; H, 4.84; N, 6.73. Found (percent): C, 57.35; H, 4.72; N, 6.50.

EXAMPLE II 1,2,3,4-tetrahydro-1l-hydroxy 2 (2 methylthioethyl) pyrazino [1,2-b]-1,2-benzothiazin-1 (2g) one 6,6-dioxide A solution of 0.90 g. (0.039 mole) of sodium in 40 ml. of methanol is saturated with methyl mercaptan, the excess methanol and methyl mercaptan are removed in vacuo, and 40 ml. of dimethylformamide is added. To this stirred solution is slowly added 15 g. (0.0386 mole) of (l,2,3,4 tetrahydro-l 1-hydroxy-1-oxopyrazino[ 1,2-b] 1,2 benzothiazin-Z-yl)ethylmethanesulfonate 6,6-dioxide. After the addition is complete the dimethylformamide is removed in vacuo, methanol is added, and the resulting solid is collected by filtration. The crude product is recrystallized from acetone-water to yield, as pure product, 1,2,3,4-tetrahydro-1 l-hydroxy-Z-(2-methy1thioethyl)pyrazino[1,2 b] 1,2-benzothiazin-l(21i)-one 6,6-dioxide, MAP. 122-123 C.

Analysis.-Calcd. for C I-I N O S (percent): C, 49.39; H, 4.74; N, 8.23. Found (percent): C, 49.53; H, 4.82; N, 8.11.

EXAMPLE IH 1,2,3,4-tetrahydro-1l-hydroxy-Z (2 phenylthioethyl) pyrazino 1,2-b] 1,2-benzothiazin-1 (2 E -one 6,6-dioxide The procedure of Example I is repeated except that an equivalent amount of thiophenol is substituted for the athiotolucne used therein to yield as product, 1,2,3,4-tetra- 

